Pancreatic cancer is the fourth leading cause of cancer death in the United States (All About Pancreatic Cancer. 2005, American Cancer Society). About 32,200 new cases will be detected and about 31,800 deaths due to this disease will occur this year. The prognosis of pancreatic cancer patients under current treatments is poor, and new drugs to treat the disease are needed. The negative prognosis of pancreatic cancer results from the fact that by the time a patient displays symptoms, the cancer has already metastasized. Treatment of pancreatic cancer involves surgery, radiation therapy, chemotherapy or a combination of the three. The current chemotherapy for advanced pancreatic cancer is gemcitabine, a drug that inhibits DNA synthesis. Gemcitabine, while more effective than past treatments, is not sufficient to treat pancreatic cancer as shown by the lethality of this cancer. Furthermore, there is no good therapy to treat pancreatic tumors that become refractory to gemcitabine (Bergenfeldt, M. and Albertsson, M. “Current state of adjuvant therapy in resected pancreatic adenocarcinoma.” Acta Oncol, 45: 124-135, 2006). The prognosis of pancreatic cancer patients under current treatments is poor, and new drugs to treat the disease are needed.
Pancreatic cancer cells have high metastatic potentials and exhibit resistance to apoptosis. In pancreatic cancer, constitutive phosphorylation of Raf-MEK-ERK is a common occurrence, and it is a contributive factor to the metastatic potential of the disease by promoting cell dissociation (Tan, X. et al. “Involvement of the mitogen-activated protein kinase kinase 2 in the induction of cell dissociation in pancreatic cancer”. Int J Oncol, 24: 65-73, 2004). and resistance to apoptosis (Boucher, M. J. et al. “MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells”. J Cell Biochem, 79: 355-369, 2000). Inhibition of this pathway hinders the growth of pancreatic cancer cells (Motomura, W. et al. “Involvement of MEK-ERK signaling pathway in the inhibition of cell growth by troglitazone in human pancreatic cancer cells”. Biochem Biophys Res Commun, 332: 89-94, 2005). In addition, pancreatic cancer cells also exhibit constitutive activation of NFκB, and its activation correlates with their metastatic potential (Fujioka, S. et al. “Function of nuclear factor kappaB in pancreatic cancer metastasis”. Clin Cancer Res, 9: 346-354, 2003), and resistance to apoptosis. Finally, the use of a dominant-negative STAT3 vector in pancreatic cancer cell lines significantly decreases their growth rate (Toyonaga, T. et al. “Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer”. Cancer Lett, 201: 107-116, 2003), implicating this pathway in the strong metastatic potential exhibited by pancreatic cancer cell lines. Therefore, any potential chemotherapies that can reduce the metastatic potential or re-sensitize pancreatic cancer cells to apoptosis have the potential of being more successful in the treatment of the disease than the currently available ones.
Certain cyclic alkaloid compositions, e.g., manzamines A-F derived from extracts of the marine sponge Haliclona sp., have been found to possess useful properties. These compounds have been described in, for example, U.S. Pat. Nos. 4,895,854; 4,895,853; and 4,895,852. Manzamines A-F have the following structures:
